tbuckley/cabot-search huggingface dataset:
General Theory of Specific Binding: Insights from a Genetic-Mechano-Chemical Protein Model
Authors: John M McBride, Jean-Pierre Eckmann, Tsvi Tlusty
Journal: Molecular Biology and Evolution (2022)

Abstract Proteins need to selectively interact with specific targets among a multitude of similar molecules in the cell. However, despite a firm physical understanding of binding interactions, we lack a general theory of how proteins evolve high specificity. Here, we present such a model that combines chemistry, mechanics, and genetics and explains how their interplay governs the evolution of specific protein–ligand interactions. The model shows that there are many routes to achieving molecular discrimination—by varying degrees of flexibility and shape/chemistry complementarity—but the key ingredient is precision. Harder discrimination tasks require more collective and precise coaction of structure, forces, and movements. Proteins can achieve this through correlated mutations extending far from a binding site, which fine-tune the localized interaction with the ligand. Thus, the solution of more complicated tasks is enabled by increasing the protein size, and proteins become more evolvable and robust when they are larger than the bare minimum required for discrimination. The model makes testable, specific predictions about the role of flexibility and shape mismatch in discrimination, and how evolution can independently tune affinity and specificity. Thus, the proposed theory of specific binding addresses the natural question of “why are proteins so big?”. A possible answer is that molecular discrimination is often a hard task best performed by adding more layers to the protein.
Short-term outcomes of chemoradiotherapy and local excision versus total mesorectal excision in T2-T3ab,N0,M0 rectal cancer: a multicentre randomised, controlled, phase III trial (the TAU-TEM study)
Authors: X. Serra-Aracil, C. Pericay, J. Badia-Closa, T. Golda, S. Biondo, P. Hernández, E. Targarona, N. Borda-Arrizabalaga, A. Reina, S. Delgado, F. Vallribera, A. Caro, J. Gallego-Plazas, M. Pascual, C. Álvarez-Laso, H.G. Guadalajara-Labajo, L. Mora-Lopez
Journal: Annals of Oncology (2022)
Cancer-associated fibroblast-specific lncRNA LINC01614 enhances glutamine uptake in lung adenocarcinoma
Authors: Tongyan Liu, Chencheng Han, Panqi Fang, Zhifei Ma, Xiaoxiao Wang, Hao Chen, Siwei Wang, Fanchen Meng, Cheng Wang, Erbao Zhang, Guozhang Dong, Hongyu Zhu, Wenda Yin, Jie Wang, Xianglin Zuo, Mantang Qiu, Jinke Wang, Xu Qian, Hongbing Shen, Lin Xu, Zhibin Hu, Rong Yin
Journal: Journal of Hematology & Oncology (2022)

Abstract Background Besides featured glucose consumption, recent studies reveal that cancer cells might prefer “addicting” specific energy substrates from the tumor microenvironment (TME); however, the underlying mechanisms remain unclear. Methods Fibroblast-specific long noncoding RNAs were screened using RNA-seq data of our NJLCC cohort, TCGA, and CCLE datasets. The expression and package of LINC01614 into exosomes were identified using flow cytometric sorting, fluorescence in situ hybridization (FISH), and quantitative reverse transcription polymerase chain reaction (RT-PCR). The transfer and functional role of LINC01614 in lung adenocarcinoma (LUAD) and CAFs were investigated using 4-thiouracil-labeled RNA transfer and gain- and loss-of-function approaches. RNA pull-down, RNA immunoprecipitation, dual-luciferase assay, gene expression microarray, and bioinformatics analysis were performed to investigate the underlying mechanisms involved. Results We demonstrate that cancer-associated fibroblasts (CAFs) in LUAD primarily enhance the glutamine metabolism of cancer cells. A CAF-specific long noncoding RNA, LINC01614, packaged by CAF-derived exosomes, mediates the enhancement of glutamine uptake in LUAD cells. Mechanistically, LINC01614 directly interacts with ANXA2 and p65 to facilitate the activation of NF-κB, which leads to the upregulation of the glutamine transporters SLC38A2 and SLC7A5 and eventually enhances the glutamine influx of cancer cells. Reciprocally, tumor-derived proinflammatory cytokines upregulate LINC01614 in CAFs, constituting a feedforward loop between CAFs and cancer cells. Blocking exosome-transmitted LINC01614 inhibits glutamine addiction and LUAD growth in vivo. Clinically, LINC01614 expression in CAFs is associated with the glutamine influx and poor prognosis of patients with LUAD. Conclusion Our study highlights the therapeutic potential of targeting a CAF-specific lncRNA to inhibit glutamine utilization and cancer progression in LUAD.
MetaRNN: differentiating rare pathogenic and rare benign missense SNVs and InDels using deep learning
Authors: Chang Li, Degui Zhi, Kai Wang, Xiaoming Liu
Journal: Genome Medicine (2022)

Multiple computational approaches have been developed to improve our understanding of genetic variants. However, their ability to identify rare pathogenic variants from rare benign ones is still lacking. Using context annotations and deep learning methods, we present pathogenicity prediction models, MetaRNN and MetaRNN-indel, to help identify and prioritize rare nonsynonymous single nucleotide variants (nsSNVs) and non-frameshift insertion/deletions (nfINDELs). We use independent test sets to demonstrate that these new models outperform state-of-the-art competitors and achieve a more interpretable score distribution. Importantly, prediction scores from both models are comparable, enabling easy adoption of integrated genotype-phenotype association analysis methods. All pre-computed nsSNV scores are available at http://www.liulab.science/MetaRNN . The stand-alone program is also available at https://github.com/Chang-Li2019/MetaRNN .
Combination of oral STING agonist MSA-2 and anti-TGF-β/PD-L1 bispecific antibody YM101: a novel immune cocktail therapy for non-inflamed tumors
Authors: Ming Yi, Mengke Niu, Yuze Wu, Hong Ge, Dechao Jiao, Shuangli Zhu, Jing Zhang, Yongxiang Yan, Pengfei Zhou, Qian Chu, Kongming Wu
Journal: Journal of Hematology & Oncology (2022)

Non-inflamed tumors, including immune-excluded and immune-desert tumors, are commonly resistant to anti-PD-1/PD-L1 (α-PD-1/PD-L1) therapy. Our previous study reported the potent antitumor activity of anti-TGF-β/PD-L1 bispecific antibody YM101 in immune-excluded tumors. However, YM101 had limited antitumor activity in immune-desert models. MSA-2 is a novel oral stimulator of interferon genes (STING) agonist, which activates the innate immune system and may synergize with YM101 in overcoming immunotherapy resistance.The dose-dependent effect of MSA-2 on STING signaling was determined by interferon-β level. The maturation and function of dendritic cell (DC) were measured by flow cytometry, RNA-seq, one-way mixed lymphocyte reaction (MLR), OVA peptide pulse, and cytokine/chemokine detection. The synergistic effect between MSA-2 and YM101 was assessed by one-way MLR. The macrophage activation was measured by flow cytometry and cytokine/chemokine detection. The in vivo antitumor activity of MSA-2 combined with YM101 was explored in syngeneic murine tumor models. After treatments, the alterations in the tumor microenvironment (TME) were detected by flow cytometry, immunohistochemistry staining, immunofluorescence staining, RNA-seq, and single-cell RNA-seq (scRNA-seq).MSA-2 could promote the maturation and antigen presentation capability of murine DC. In the one-way MLR assay, MSA-2 synergized with YM101 in enhancing naive T cell activation. Moreover, MSA-2 stimulated the classical activation of macrophage, without significant influence on alternative activation. Further in vivo explorations showed that MSA-2 increased multiple proinflammatory cytokines and chemokines in the TME. MSA-2 combined with YM101 remarkedly retarded tumor growth in immune-excluded and immune-desert models, with superior antitumor activity to monotherapies. Flow cytometry, bulk RNA-seq, and scRNA-seq assays indicated that the combination therapy simultaneously boosted the innate and adaptive immunity, promoted antigen presentation, improved T cell migration and chemotaxis, and upregulated the numbers and activities of tumor-infiltrating lymphocytes.Our results demonstrate that MSA-2 synergizes with YM101 in boosting antitumor immunity. This immune cocktail therapy effectively overcomes immunotherapy resistance in immune-excluded and immune-desert models.
Small-molecule inhibitors, immune checkpoint inhibitors, and more: FDA-approved novel therapeutic drugs for solid tumors from 1991 to 2021
Authors: Qing Wu, Wei Qian, Xiaoli Sun, Shaojie Jiang
Journal: Journal of Hematology & Oncology (2022)

Abstract The United States Food and Drug Administration (US FDA) has always been a forerunner in drug evaluation and supervision. Over the past 31 years, 1050 drugs (excluding vaccines, cell-based therapies, and gene therapy products) have been approved as new molecular entities (NMEs) or biologics license applications (BLAs). A total of 228 of these 1050 drugs were identified as cancer therapeutics or cancer-related drugs, and 120 of them were classified as therapeutic drugs for solid tumors according to their initial indications. These drugs have evolved from small molecules with broad-spectrum antitumor properties in the early stage to monoclonal antibodies (mAbs) and antibody‒drug conjugates (ADCs) with a more precise targeting effect during the most recent decade. These drugs have extended indications for other malignancies, constituting a cancer treatment system for monotherapy or combined therapy. However, the available targets are still mainly limited to receptor tyrosine kinases (RTKs), restricting the development of antitumor drugs. In this review, these 120 drugs are summarized and classified according to the initial indications, characteristics, or functions. Additionally, RTK-targeted therapies and immune checkpoint-based immunotherapies are also discussed. Our analysis of existing challenges and potential opportunities in drug development may advance solid tumor treatment in the future.
Light‐Programmable Nanocomposite Hydrogel for State‐Switchable Wound Healing Promotion and Bacterial Infection Elimination
Authors: Zhekun Zhang, Juning Xie, Jun Xing, Changhao Li, Tak Man Wong, Hui Yu, Yuanxing Li, Fabang Yang, Yu Tian, Huan Zhang, Wei Li, Chengyun Ning, Xiaolan Wang, Peng Yu
Journal: Advanced Healthcare Materials (2022)

Abstract Developing an ideal wound dressing that not only accelerates wound healing but also eliminates potential bacterial infections remains a difficult balancing act. This work reports the design of a light‐programmable sodium alginate nanocomposite hydrogel loaded with BiOCl/polypyrrole (BOC/PPy) nanosheets for state‐switchable wound healing promotion and bacterial infection elimination remotely. The nanocomposite hydrogel possesses programmable photoelectric or photothermal conversion due to the expanded light absorption range, optimized electron transmission interface, promoted photo‐generated charge separation, and transfer of the BOC/PPy nanosheets. Under white light irradiation state, the nanocomposite hydrogel induces human umbilical vein endothelial cells migration and angiogenesis, and accelerates the healing efficiency of mouse skin in vivo. Under near‐infrared light irradiation state, the nanocomposite hydrogel presents superior antibacterial capability in vitro, and reaches an antibacterial rate of 99.1% for Staphylococcus aureus infected skin wound in vivo. This light‐programmable nanocomposite hydrogel provides an on‐demand resolution of biological state‐switching to balance wound healing and elimination of bacterial infection.
Epicardial delivery of a conductive membrane synchronizes conduction to reduce atrial fibrillation
Authors: Yi-Chong Zhang, Min-Yao Wang, Chong-Yu Zhang, Yun-Fei Fan, Jun Wu, Shu-Hong Li, Anne Fu, Yu Sun, Terrance M. Yau, Ting-Hsuan Lu, Hsing-Wen Sung, Ren-Ke Li
Journal: Journal of Controlled Release (2022)
Glioma diagnosis and therapy: Current challenges and nanomaterial-based solutions
Authors: Tianzhong Li, Jingfeng Li, Zhi Chen, Shaohui Zhang, Shunling Li, S. Wageh, Omar A. Al-Hartomy, Abdullah G. Al-Sehemi, Zhongjian Xie, Ranjith Kumar Kankala, Han Zhang
Journal: Journal of Controlled Release (2022)
Cell‐Derived Vesicles with Increased Stability and On‐Demand Functionality by Equipping Their Membrane with a Cross‐Linkable Copolymer
Authors: Xinan Huang, Dimitri Hürlimann, Hendrik T. Spanke, Dalin Wu, Michal Skowicki, Ionel Adrian Dinu, Eric R. Dufresne, Cornelia G. Palivan
Journal: Advanced Healthcare Materials (2022)

Cell-derived vesicles retain the cytoplasm and much of the native cell membrane composition. Therefore, they are attractive for investigations of membrane biophysics, drug delivery systems, and complex molecular factories. However, their fragility and aggregation limit their applications. Here, the mechanical properties and stability of giant plasma membrane vesicles (GPMVs) are enhanced by decorating them with a specifically designed diblock copolymer, cholesteryl-poly[2-aminoethyl methacrylate-b-poly(ethylene glycol) methyl ether acrylate]. When cross-linked, this polymer brush enhances the stability of the GPMVs. Furthermore, the pH-responsiveness of the copolymer layer allows for a controlled cargo loading/release, which may enable various bioapplications. Importantly, the cross-linked-copolymer GPMVs are not cytotoxic and preserve in vitro membrane integrity and functionality. This effective strategy to equip the cell-derived vesicles with stimuli-responsive cross-linkable copolymers is expected to open a new route to the stabilization of natural membrane systems and overcome barriers to biomedical applications.
Cancer stem cell antigen nanodisc cocktail elicits anti-tumor immune responses in melanoma
Authors: Marisa E. Aikins, You Qin, Hannah E. Dobson, Alireza Hassani Najafabadi, Kexing Lyu, Yao Xu, Ying Xin, Anna Schwendeman, Max S. Wicha, Alfred E. Chang, Qiao Li, James J. Moon
Journal: Journal of Controlled Release (2022)
Combining drug salt formation with amorphous solid dispersions – a double edged sword
Authors: Tze Ning Hiew, Lynne S. Taylor
Journal: Journal of Controlled Release (2022)

Glass transition temperature (Tg) is important for amorphous compounds because it can have implications on their physical and chemical stability. With drugs that possess ionizable acidic or basic groups, salt formation is a potential strategy to reduce re-crystallization tendency through Tg elevation. While salt formation has been reported to impact re-crystallization tendency, it is not known if this holds true for all drugs and if it is useful in the context of amorphous solid dispersion (ASD) formulations. In addition, little information on the impact of salt formation on drug release performance of ASD is available. Herein, the influence of salt formation and Tg elevation on the release performance of lumefantrine (Tg = 19.7 °C) when formulated as an ASD with copovidone (PVPVA) was examined. Lumefantrine salts and lumefantrine salt–PVPVA ASDs with drug loadings (DLs) ranging from 5 to 30% were prepared. The acids used for salt formation were benzoic acid, benzenesulfonic acid, camphorsulfonic acid, hydrochloric acid, p-toluenesulfonic acid, poly(ethylene) glycol 250 diacid (PEG 250 diacid), and sulfuric acid. Salt formation resulted in an elevation of Tg compared to lumefantrine free base, with the largest increase in Tg observed with lumefantrine sulfate. With a lower Tg salt, ASDs could be formulated at higher DLs while ensuring drug release. In contrast, drug release ceased at a DL as low as 5% when Tg of the salt was high. However, ASDs with lower Tgs such as the benzoate and PEG 250 diacid salts showed poor stability against re-crystallization when stored under stress storage conditions. When using a salt in an ASD formulation, attention should be paid to the Tg of the salt, since it may show opposing effects on physical stability and drug release, at least for PVPVA-based ASDs.
Effects of gender-affirming hormone therapy on cardiovascular risk factors focusing on glucose metabolism in an Austrian transgender cohort
Authors: Carola Deischinger, Dorota Slukova, Ivica Just, Ulrike Kaufmann, Juergen Harreiter, Mick van Trotsenburg, Siegfried Trattnig, Martin Krššák, Alexandra Kautzky-Willer, Radka Klepochova, Lana Kosi-Trebotic
Journal: International Journal of Transgender Health (2022)

We aimed to investigate the effect of gender-affirming hormone therapy (GAHT) on cardiovascular disease risk factors focusing on glucose tolerance.This primarily translational study enrolled 16 transgender persons assigned female at birth (AFAB), 22 assigned male at birth (AMAB), and 33 age- and BMI-matched cisgender controls at the Medical University of Vienna from 2013 to 2020. A 3-Tesla MRI scan to measure intramyocardial, pancreatic, hepatic fat content and subcutaneous-to-visceral adipose tissue ratio (SAT/VAT-ratio), an oral glucose tolerance test (oGTT), bloodwork including brain natriuretic peptide (pro-BNP), sex hormones and two glucose-metabolism related biomarkers (adiponectin, betatrophin) were performed.Estrogen intake was associated with higher fasting insulin (p = 0.034) and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (p = 0.037), however, lower HbA1c levels (p = 0.031) in AMAB than cisgender males. Adiponectin (p = 0.001) and betatrophin (p = 0.034) levels were higher in AMAB than cisgender males, but similar to cisgender females. Compared to cisgender females, AFAB displayed no differences in glucose metabolism or SAT/VAT-ratio. AFAB had lower pro-BNP levels (p = 0.014), higher liver enzymes (AST: p = 0.011; ALT: p = 0.012) and lower HDL levels (p = 0.017) than cisgender females, but comparable levels to cisgender males. AMAB showed an increased heart rate (p < 0.001) and pro-BNP (p = 0.002) levels, but a more favorable SAT/VAT-ratio (p = 0.013) and lower creatine kinase (CK) (p = 0.001) than cisgender males. There were no relevant differences in organ fat content between transgender persons and their respective cisgender controls.In AMAB, most investigated parameters adapted to levels seen in cisgender females except for parameters related to fasted insulin resistance. AMAB should be monitored with respect to the development of insulin resistance.
Sepsis-induced immunosuppression: mechanisms, diagnosis and current treatment options
Authors: Di Liu, Si-Yuan Huang, Jian-Hui Sun, Hua-Cai Zhang, Qing-Li Cai, Chu Gao, Li Li, Ju Cao, Fang Xu, Yong Zhou, Cha-Xiang Guan, Sheng-Wei Jin, Jin Deng, Xiang-Ming Fang, Jian-Xin Jiang, Ling Zeng
Journal: Military Medical Research (2022)

Sepsis is a common complication of combat injuries and trauma, and is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. It is also one of the significant causes of death and increased health care costs in modern intensive care units. The use of antibiotics, fluid resuscitation, and organ support therapy have limited prognostic impact in patients with sepsis. Although its pathophysiology remains elusive, immunosuppression is now recognized as one of the major causes of septic death. Sepsis-induced immunosuppression is resulted from disruption of immune homeostasis. It is characterized by the release of anti-inflammatory cytokines, abnormal death of immune effector cells, hyperproliferation of immune suppressor cells, and expression of immune checkpoints. By targeting immunosuppression, especially with immune checkpoint inhibitors, preclinical studies have demonstrated the reversal of immunocyte dysfunctions and established host resistance. Here, we comprehensively discuss recent findings on the mechanisms, regulation and biomarkers of sepsis-induced immunosuppression and highlight their implications for developing effective strategies to treat patients with septic shock.
N‐acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4‐acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA
Authors: Xiao Zheng, Qi Wang, You Zhou, Dachuan Zhang, Yiting Geng, Wenwei Hu, Changping Wu, Yufang Shi, Jingting Jiang
Journal: Cancer Communications (2022)

Abstract Background N‐acetyltransferase 10 ( NAT10 ) is the only enzyme known to mediate the N4‐acetylcytidine (ac4C) modification of mRNA and is crucial for mRNA stability and translation efficiency. However, its role in cancer development and prognosis has not yet been explored. This study aimed to examine the possible role of NAT10 in colon cancer. Methods The expression levels of NAT10 were evaluated by immunohistochemical analyses with a colon cancer tissue microarray, and its prognostic value in patients was further analyzed. Quantitative real‐time polymerase chain reaction (qRT‐PCR) and Western blotting were performed to analyze NAT10 expression in harvested colon cancer tissues and cell lines. Stable NAT10 ‐knockdown and NAT10 ‐overexpressing colon cancer cell lines were constructed using lentivirus. The biological functions of NAT10 in colon cancer cell lines were analyzed in vitro by Cell Counting Kit‐8 (CCK‐8), wound healing, Transwell, cell cycle, and ferroptosis assays. Xenograft models were used to analyze the effect of NAT10 on the tumorigenesis and metastasis of colon cancer cells in vivo. Dot blotting, acetylated RNA immunoprecipitation‐qPCR, and RNA stability analyses were performed to explore the mechanism by which NAT10 functions in colon cancer progression. Results NAT10 was upregulated in colon cancer tissues and various colon cancer cell lines. This increased NAT10 expression was associated with shorter patient survival. Knockdown of NAT10 in two colon cancer cell lines (HT‐29 and LoVo) impaired the proliferation, migration, invasion, tumor formation and metastasis of these cells, whereas overexpression of NAT10 promoted these abilities. Further analysis revealed that NAT10 exerted a strong effect on the mRNA stability and expression of ferroptosis suppressor protein 1 ( FSP1 ) in HT‐29 and LoVo cells. In these cells, FSP1 mRNA was found to be modified by ac4C acetylation, and this epigenetic modification was associated with the inhibition of ferroptosis. Conclusions Our study revealed that NAT10 plays a critical role in colon cancer development by affecting FSP1 mRNA stability and ferroptosis, suggesting that NAT10 could be a novel prognostic and therapeutic target in colon cancer.
Determining the cortical, spinal and muscular adaptations to strength-training in older adults: A systematic review and meta-analysis
Authors: Ummatul Siddique, Ashlyn K. Frazer, Janne Avela, Simon Walker, Juha P. Ahtiainen, Glyn Howatson, Jamie Tallent, Dawson J. Kidgell
Journal: Ageing Research Reviews (2022)